Dendritic cells (DCs) abundantly express diverse receptors to recognize mannans in the outer surface of Candida cell wall, and these interactions dictate the host immune responses that determine disease outcomes. C. krusei prevalence in candidiasis worldwide has increased since this pathogen has developed multidrug resistance. However, little is known how the immune system responds to C. krusei. Particularly, the molecular mechanisms of the interplay between C. krusei mannan and DCs remain to be elucidated. We investigated how C. krusei mannan affected DC responses in comparison to C. albicans, C. tropicalis and C. glabrata mannan. Our results showed that only C. krusei mannan induced massive cytokine responses in DCs, and led to apoptosis. Although C. krusei mannan-activated DCs underwent apoptosis, they were still capable of initiating Th17 response. C. krusei mannan-mediated DC apoptosis was obligated to the TLR2 and MyD88 pathway. These pathways also controlled Th1/Th17 switching possibly by virtue of the production of the polarizing cytokines IL-12 and IL-6 by the C. krusei mannan activated-DCs. Our study suggests that TLR2 and MyD88 pathway in DCs are dominant for C. krusei mannan recognition, which differs from the previous reports showing a crucial role of C-type lectin receptors in Candida mannan sensing.
Mannan (mannosylated glycoproteins) in the outermost layer of the Candida cell wall may be the first molecules that interact with host dendritic cells (DCs) and activate immune responses that determine disease outcomes. However, little is known about how different mannan structures of common oral Candida species affect DC activation. The effects of heat-inactivated (HI) yeast cells and soluble mannan of Candida albicans, Candida parapsilosis, and Candida dubliniensis on bone marrow-derived DC (BMDC) responses were compared. HI Candida and the mannan exhibited different effects on BMDC activation and functions, which could be due to other carbohydrate compositions in the yeast cell wall. Among Candida mannan, the C. albicans mannan was the weakest stimulus and induced only interferon (IFN)-γ production. This suggests the possibility that C. albicans mannan may skew T helper (Th) responses from protective Th17 toward Th1. In contrast, C. parapsilosis mannan caused strong BMDC activation and high production of several proinflammatory cytokines which possibly promote hyperinflammation. Meanwhile, C. dubliniensis mannan induced moderate BMDC responses, which may correlate with its lower pathogenicity. Therefore, mannan of each Candida species play distinct roles in DC responses and may be involved in the immunopathogenesis and disease severity of oral candidiasis as well as other Candida infection.
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